Bolus administration of remimazolam was superior to midazolam for deep sedation in elderly patients undergoing diagnostic bronchoscopy: A randomized, double-blind, controlled trial

Background: To date, there is no standardized practice for the use of pharmacological sedatives during flexible bronchoscopy, particularly for elderly patients. This exploratory study aimed to assess the efficacy and safety of remimazolam at a single induced dose for deep sedation in elderly patients undergoing diagnostic flexible bronchoscopy (DFB), and compare with midazolam, a commonly used sedative. Methods: A total of 100 elderly patients (age range 65–80 yr; American Society of Anesthesiologists Physical Status I–III) undergoing DFB were randomly allocated into 2 groups according to the sedatives used for induction: the remimazolam group and the midazolam group. Sedation induction was initiated by an intravenous bolus of remimazolam (0.135 mg/kg) or midazolam (0.045 mg/kg), respectively, both groups were combined with a high-dose of alfentanil (18 µg/kg), and supplemented with high-flow nasal cannula (HFNC) oxygen supply at a flow rate of 45 L/min. If the target depth of sedation was not achieved, propofol would be titrated as a rescue. The primary outcome was the success rate of sedation at a single induced dose to achieve target depth (Ramsay sedation score [RSS] = 4) during induction, intraoperative changes in vital signs, postoperative follow-up situation and incidence of post-bronchoscopy adverse events were evaluated as secondary outcomes. Results: The success rate of sedation in the remimazolam group was significantly higher than that in the midazolam group (65.2% vs 39.6%, P = .013), while the incidence of extra sleep within 6 hours after procedure was lower in the remimazolam group as compared to the midazolam group (10.9% vs 31.3%, P = .016). No statistically significant differences were observed between the 2 groups regarding hemodynamic fluctuations, incidence of hypoxemia, and cough response during the procedure, as well as postoperative recall, willingness to undergo reexamination, and other post-bronchoscopy adverse events. Conclusions: Bolus administration of remimazolam offers advantages over midazolam for deep sedation in elderly patients undergoing DFB, in terms of a higher success rate of sedation and a lower incidence of extra sleep within 6 hours after procedure, though the safety profiles of both groups were favorable.


Introduction
Flexible bronchoscopy (FB) is an essential, invasive procedure used in clinical practice for the diagnosis and treatment of bronchial, pulmonary, thoracic, and other diseases in clinical practice. [1,2]Owing to concern of violent stimulation during FB procedure, sedation is recommended by most guidelines or expert consensus to be offered to all patients WQ and XR contributed equally to this work.

This work was funded by a grant from Ningbo Health Science and Technology Project, China (grant number 2022Y35) and the Medical and Health Science and Technology Project of Zhejiang Province, China (grant number 2024XY036).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.without contraindications. [2,3]However, for elderly patients with fragile cardiopulmonary function, hypometabolism, and increased central sensitivity to anesthetic drugs, there are few preferred pharmacological agents for bronchoscopy sedation.Commonly used sedatives, such as propofol (associated with noticeable circulatory and respiratory depression), dexmedetomidine (with a prolonged induction time and susceptibility to hypotension and bradycardia), and midazolam (slow onset and long duration of action), have drawbacks that restrict their application in elderly patients. [4,5]Fortunately, several emerging agents are being considered as acceptable alternatives, such as remimazolam, a new benzodiazepine for intravenous use in procedural sedation, has the rapid onset-offset properties comparable to propofol but with minor respiratory/circulatory depression. [6,7]Some studies have confirmed that remimazolam could be safely and effectively used for bronchoscopy and had a faster onset of action and faster recovery of neuropsychiatric functions compared to midazolam. [8,9]However, whether remimazolam may be the preferred pharmacological agents for bronchoscopy sedation in elderly patients has not been reported in the literature.The present study aimed to compare the efficacy and safety of remimazolam versus midazolam at a single induced dose for deep sedation in elderly patients undergoing diagnostic flexible bronchoscopy (DFB).

Study design and patients
This was a randomized, double-blind, controlled trial.The protocol was approved by the institutional Ethics Committee of Beilun District People's Hospital (Approval number: 2021-09 [YS]) and registered to chictr.org(ChiCTR2100049052).The clinical trial was conducted in accordance with the Declaration of Helsinki between May 2022 and July 2022 at Beilun District People's Hospital, an 840-bed tertiary care teaching hospital.Written informed consent was obtained from all participants before enrollment.
A total of 100 elderly patients (age range 65-80 yr; American Society of Anesthesiologists [ASA] physical status I-III) were recruited, and finally 94 were eligible and analyzed for this study.Indications for DFB included pneumonia (58.5%), bronchiectasis (20.2%), pulmonary shadow (6.4%), hemoptysis (6.4%), and miscellaneous (8.5%).The exclusion criteria were as follows: patients with measured peripheral capillary oxygen saturation (SpO 2 ) <90% in room air; patients with a history of alcohol abuse or current use of any psychiatric medication; patients with severe cardiac disease, including aortic stenosis, mitral stenosis, haemodynamic instability caused by severe arrhythmia, and acute myocardial infarction or cardiac surgery within the last 6 months; patients with neurologic disorders (schizophrenia, Parkinson's disease, or myasthenia gravis) or other conditions contributing to difficulty in assessing a conscious response; patients refusing to give informed consent.
Patients undergoing DFB were randomly allocated into either the remimazolam group or the midazolam group in a 1:1 ratio.A randomized allocation sequence was created by an independent research assistant who was not involved in the study using a random number sequence generated from a computer, and the study drug was prepared outside the bronchoscopy suite by a nurse uninvolved in the DFB procedure, based on the closed envelope method.The syringe of remimazolam or midazolam was labeled with the patient's inclusion number with the same volume (dispensed with normal saline to 15 mL) and then passed to the anesthesiologist in charge of sedation.Patients, anesthesiologist in charge of sedation, as well as bronchoscopists were blinded to the sedation regimen.The demographic information, vital signs, and follow-up data of the patients were recorded on a paper case report form by an attending anesthesiologist.

Procedure and sedation
All patients were fasted for 8 hours for solids and for 2 hours for clear fluids without any premedication before the procedure.On the morning of their scheduled DFB, routine monitoring, including electrocardiogram, noninvasive blood pressure, respiratory rate, pulse oxygen saturation and end-tidal carbon dioxide, were performed upon the arrival of each patient in the operating room.For the purpose of topical anesthesia, patients all received 5 mL of 2% lidocaine induced by nebulized inhalation for 15 minutes before procedure, and 1 mL of 2% lidocaine solution were applied by nasal swap in each nose after the patients were lying on their dorsal position.All patients received humidified oxygen at a flow rate of 45 L/min and a concentration of 100% using a high-flow nasal cannula (HFNC) (AIRVO 2 , Fisher & Paykel, New Zealand) for 2 minutes before the commencement of sedation.Then, either a single dose of midazolam (0.045 mg/kg) (Nhwa Pharmaceutical Co., Ltd., Jiangsu, China, lot number: H19990027) or remimazolam (0.135 mg/kg) (Hengrui Pharmaceuticals Co., Ltd., Jiangsu, China, lot number: H20190034) was intravenously administered using a syringe pump at a speed of 20 mL/min (equivalent to 1200 mL/h).1-minute later, a bolus of intravenous alfentanil (18 µg/kg) (Yichang Renfu Pharmaceuticals Co., Ltd., Yichang, China, lot number: H20190034) was administered using the same syringe pump technique.The target depth of sedation was set as a Ramsay sedation score (RSS) = 4 (Patient asleep, shows no response to verbal or tactile stimulus), if achieved, sedation was considered successful, otherwise propofol would be titrated as a rescue until the RSS score achieved 4.Then, DFB procedure was performed by the same experienced bronchoscopists (a chief physician in the department of respiratory at our hospital) using EVIS LUCERA BF-260 series bronchoscope (BF260, BF1T260, and BF-P260F; Olympus; Tokyo, Japan) via the nasal route, and 2% lidocaine was sprayed through the bronchoscope channel to enhance topical anesthesia with the "spray-as-you-go" technique over the vocal cords and the tracheobronchial tree.Various diagnostic procedures, including bronchial biopsy, bronchial brushing, and bronchoalveolar lavage, were performed based on individual clinical conditions.All DFB procedures were completed by 12:00 noon.
During DFB procedure, intraoperative (From the end of induction until the patients regained consciousness) hypertension/hypotension was defined as a systolic blood pressure more than 160 mm Hg/less than 90 mm Hg, and then urapidil/ dopamine was given intravenously 1 mg each time until blood pressure stabilized.And episodes of hypoxemia, defined as an SpO 2 <90% for >10 seconds, would be treated with Jaw thrust maneuver or temporary mask ventilation, and if hypoxemia remained uncorrected, laryngeal mask insertion or tracheal intubation would be determined by the anesthesiologist.
At the end of the bronchoscopy procedure, the specific antagonist of flumazenil (5 μg/kg) and naloxone (3 μg/kg) would be given immediately.Patients were transferred to the recovery room as they regained consciousness (RSS ≦ 2), and continuously monitored and received supplemental oxygen (4 L/ min) through a conventional nasal catheter for 15 minutes.Subsequently, they were transferred to the inpatient ward and with a 3 hours constant monitoring.Postoperative follow-up was performed 6 hours after the procedure to avoid any judgement alteration due to residual effects of the drugs.

Data collection and measured outcomes
The primary outcome assessed was the success rate of sedation at a single induced dose, defined as achieving the target depth of sedation (RSS = 4) with a single induced dose of sedatives and no need for a rescue sedative medication (propofol).The secondary outcomes included intraoperative changes in vital signs, such as hemodynamic stability and the use of vasoactive drugs, the incidence of hypoxemia and the minimum SpO 2 value, cough severity evaluated by visual analogue scale (VAS) with a score from 0 to 10 indicating no cough to severe cough, induction time was defined as the initiation of bolus sedatives to the beginning of the FB procedure, while recovery time was defined as the end of the procedure and administration of antagonists (flumazenil and naloxone) until the patient's RSS score ≦ 2. Postoperative follow-up situations were also used as secondary outcomes, such as incidence of postoperative extra sleep within 6 hours postoperatively, postoperative recall and willingness to undergo reexamination, and post-bronchoscopy adverse events, such as nausea, vomiting, fatigue, and dizziness.

Statistical analysis
Statistical analyses were conducted using SPSS Statistics Version 25.0 (IBM Co.).The data are presented as mean (standard deviation) for continuous variables and as the number of patients (%) for categorical variables.Continuous data were analyzed using independent sample t test, while categorical data were analyzed using the chi-squared test or Fisher's exact test, as appropriate.A significance level of P < .05 was used to determine statistical significance.

Demographic characteristics
Of the 100 patients randomized into the study, 6 withdrew before completion, as described in Figure 1.Four patients in the remimazolam group withdrew from the trial, one of them was converted to transoral FB procedure due to bilateral nasal meatus stenosis, 2 patients were converted to mass resection due to endobronchial masses found during FB procedure, and 1 patient was converted to ultrasound-guided transbronchial needle biopsy due to intrabronchial abnormalities found during FB procedure.While in the midzolam group, only 2 patients withdrew from the trial, 1 was converted to mass resection due to endobronchial masses and 1 to ultrasound-guided transbronchial needle biopsy due to intrabronchial abnormalities found during FB procedure.
There were no obvious differences in baseline characteristics (age, sex, weight, body mass index (BMI), and ASA physical status) between the 2 groups (P > .05),as shown in Table 1.The primary indications for DFB were pneumonia, followed by bronchiectasis, lung shadow and hemoptysis.Diagnostic procedures included bronchoalveolar lavage, bronchial brushing and bronchial biopsy.The indications and procedures were uniformly distributed in both groups (P > .05),as shown in Table 1.

Intraoperative clinical data and outcome measures
All eligible patients in both groups underwent diagnostic evaluation of the tracheobronchial tree successfully and woke up within 7 minutes after bronchoscopy.The mean induction time and total inspection time of bronchoscopy in group RA were 3.9 ± 1.2 minutes and 5.7 ± 2.2 minutes respectively, compared with 4.2 ± 1.4 minutes and 5.6 ± 2.3 minutes in group MA, and no significant differences were found between the 2 groups (P > .05).The success rate of sedation with bolus administration of remimazolam was significantly higher than that with midazolam (65.2% vs 39.6%, P = .013).There were no statistically significant differences between the 2 groups in terms of circulatory fluctuations (proportion of patients using urapidil or dopamine), incidence of hypoxemia (8.7% vs 8.3%), minimum SpO 2 value, cough VAS score (1.4 ± 1.3 vs 1.2 ± 1.1), and awake time between the 2 groups, as shown in Table 2.

Follow-up (6 h after the procedure) and adverse events
Within 6 hours postoperatively, the incidence of extra sleep in remimazolam group was lower than that in midazolam group (10.9% vs 31.3%,P = .016),but no statistically significant differences were observed between the groups regarding postoperative recall and willingness to undergo reexamination, as well as other post-bronchoscopy adverse events, including nausea, vomiting, fatigue, and dizziness (P > .05,see Table 3).

Discussion
Our prospective randomized controlled study showed for the first time that bolus administration of remimazolam was superior to midazolam for deep sedation in elderly patients undergoing DFB, mainly in terms of higher success rate of sedation at a single induced dose to achieve target level of deep sedation, and lower incidence of extra sleep within 6 hours postoperatively, though both sedation regimens are relatively safe and effective when combined with high doses of alfentanil and supplemented with remedial sedatives and high-flow humidified oxygen.Considering single intravenous bolus induction is usually required for its convenience in clinical practice, our findings may provide valuable insights into the selection of sedative agents or regimens for DFB in elderly patients.
Regarding the comparison of sedative efficacy of these 2 benzodiazepines, many literatures believed that remimazolam was superior to midazolam.Studies by Keam SJ showed that the onset of remimazolam was significantly faster than midazolam, and non-inferior to propofol. [10]The comparative study of adult bronchoscopy under moderate sedation conducted by Pastis NJ also confirmed that, the sedation success rate of remimazolam (80.6%) was significantly higher than that of midazolam (32.9%). [11]However, there have been no comparative studies of these 2 benzodiazepines for sedation in elderly patients undergoing bronchoscopy.Our study showed that, as compared to midazolam (0.045 mg/kg), intravenous bolus injection of remimazolam (0.135 mg/kg) demonstrated a higher success rate in achieving target level of deep sedation, the results were consistent with the previously published studies in adults. [11]However, it should be emphasized that the doses of the 2 benzodiazepine sedatives involved in this study were not equipotent.To date, the equipotent dose of midazolam and remimazolam is not known, especially in elderly patients and in combination with afentanil.The doses of midazolam (0.045 mg/ kg) and remimazolam (0.135 mg/kg) used in this study were determined based on guidelines and expert consensus, as well as our previous clinical experience. [2,4,12]The per capita dose of midazolam was 2.7 mg in our study, which has exceeded the recommended dose for elderly patients in the British Thoracic Society Guidelines. [13]As for remimazolam, the optimal doses required for the induction of general anesthesia or procedural sedation for endoscopy in elderly patients remain unclear.In Chinese patients, the ED 95 of remimazolam tosilate for anesthesia induction was 0.118 mg/kg (95% CI 0.103-0.649)and 0.090 mg/kg (95% CI 0.075-0.199) in elderly patients aged 60 to 69 and 70 to 85 years, respectively. [14]Obviously, the dose of remimazolam (0.135 mg/kg) adopted for bolus administration in our study were higher than these ED 95 values, and even in combination with a fixed high dose of afentanil, 34.8% of elderly patients still failed to achieve the target level of deep sedation.Therefore, the optimal doses required for DFB sedation in elderly patients need to be further observed and clarified.But it's important to note that, although our findings showed that both sedation regimens of remimazolam and midazolam were relatively safe, it is clear that further increases in the doses of these 2 benzodiazepines could easily lead to a dramatic increase in the risk of hypoxemia and post-bronchoscopy adverse events.
Most guidelines and expert consensus recommend mild to moderate sedation (RSS between 2 and 3 points) for bronchoscopy. [2,4,13,15]The rationale behind this recommendation is the concern that deep sedation or oversedation may lead to significant respiratory and circulatory depression.Moreover, desaturation risk with moderate sedation is particularly prone to occur in elderly patients and those with an ASA III score. [16,17]However, in many cases, mild to moderate sedation is hard to effectively inhibit the intense airway irritation and severe cough caused by bronchoscopic procedure, resulting in significant intraoperative circulatory fluctuations and cardiovascular hazards, which cannot be ignored especially for elderly patients with fragile cardiovascular function.
In this context, the maintenance of intraoperative circulatory stability in the elderly patients is the focus of perioperative sedation or anesthesia. [18,19]Our results showed that the circulation fluctuation and cough VAS scores in both groups were relatively low, and severe cough with a VAS score exceeding 5 was quite rare, which could be attributed to the coadministration of high doses of alfentanil and deep sedation level.It is widely acknowledged that the typical sedation regimens for FB is difficult to solve cough and stress problems in the absence of opioids. [3,13,15]As a short-acting opioid with mild respiratory depression, alfentanil possesses notable antistress and anti-coughing effects, but only at high doses can the desired effect be achieved, which has been confirmed in our previous research and other literatures. [12,20,21]In this study, the combined application of high doses of alfentanil proved effective in achieving deep sedation and contributed to ideal anti-stress effect and hemodynamic stabilization.Notably, the numbers of patients required vasoactive drugs (urapidil or dopamine) administered intraoperatively due to hypertension or hypotension were very few.Thus, it was evident that for elderly patients with fragile cardiopulmonary function, the application of hgh doses of afentanil was safe and feasible.Additionally, we advocate for propofol as a preferred rescue choice when the target sedation depth is not achieved after bolus administration of sedatives and alfentanil, for low doses of propofol supplemented will not cause significant respiratory and circulatory depression, [22] and helps to avoid prolonged postoperative lethargy or delayed cognitive recovery due to excessive doses of remimazolam or midazolam. [23,24]n this study, deep sedation with non-intubation and preserved spontaneous breathing was adopted for elderly bronchoscopy patients, and no similar literature has been reported so far.Though at the same level of deep sedation, patients in both groups showed comparable hemodynamic stability, minimal hypoxic incidence, as well as satisfactory bronchoscopy conditions, and high willingness to undergo reexamination.However, the major risks of respiratory depression and hypoxemia associated with deep sedation should be emphasized.In order to effectively prevent the hypoxic risk, a new oxygen supply technique, namely HFNC, was also used in this study, which can significantly improve the safety of deep sedation and further improve the conditions of bronchoscopy manipulation. [24,25]In our study, HFNC set at a flow rate of 45 L/min substantially reduced the incidence of hypoxemia to less than 10% in both 2 groups under deep sedation, and in all cases in which hypoxia occurred, normal oxygenation was rapidly restored only by jaw support or temporary maskassisted ventilation, and none required laryngeal mask insertion or endotracheal intubation.The anti-hypoxia effect of HFNC has been confirmed in many studies, a study from Spence EA found that the effectiveness of HFNC in improving oxygenation and prolongating the duration of safe apnea during general anesthesia induction. [26]26] Moreover, HFNC also helps to avoid insufficient ventilation and partial airway obstruction caused by sedation with high doses of opioids. [27]These effects emphasize the pivotal role of HFNC in enhancing the safety and efficacy of bronchoscopy under deep sedation.
Our results also confirmed that the incidence of extra sleep after procedure was significantly reduced in the remimazolam group than that in the midazolam group, this could be attributed to the prolonged sedative effect of midazolam and its active metabolites due to its organ dependency and considerably lower drug clearance rate, particularly in elderly patients.Williams' studies confirmed that the average serum benzodiazepine concentration 2 hours after sedation was approximately 2-fold higher in patients aged ≥70 years than in those aged <40 years, and for this reason, elderly patients were likely to require lower doses of sedatives for bronchoscopy. [28]Considering the short duration and intense irritation of bronchoscopy procedure, agents such as remimazolam, that provides an appropriate depth of sedation with a rapid onset and recovery, are preferrable.It is now clear that remimazolam is rapidly metabolized to a pharmacologically inactive metabolite by carboxylesterase-1A, independent of the cytochrome P450 enzyme, which makes the recovery from remimazolam sedation faster and more predictable than midazolam. [29,30]Our study confirmed that both sedative drugs could be safely used and meet the needs of DFB sedation by bolus administration, and only one case had intraoperative painful recall found in postoperative follow-up, which may be related to the deep sedation level adopted in this study.Given the convenience of single intravenous bolus induction for procedural sedation, it is believable that the combined sedation regimen of remimazolam and alfentanil with bolus administration is feasible and superior in elderly patients.
This study presents several limitations.First, while our data analysis indicated the superiority of bolus remimazolam injection over midazolam, larger sample sizes, multicenter studies, as well as well-designed randomized controlled clinical trials are needed to confirm and support these findings.Second, patients with respiratory failure were excluded from the study.Therefore, the findings of this study may primarily pertain to patients with near normal respiratory function and not requiring pre-bronchoscopy oxygen supplementation.Third, the induction dose of midazolam used in this study should not be further increased, but whether the induction dose of remimazolam can be increased to improve the success rate of inducing sedation without causing other adverse reactions such as hypoxemia, delayed recovery and postoperative extra sleep, needs further observation and study.And last, both benzodiazepines and alfentanil can potentially lead to postoperative delirium or cognitive impairment. [31,32]Although this study did not observe significant postoperative cognitive changes or postoperative delirium, this possibility cannot be entirely ruled out and warrants further observation.

Conclusion
With the assistance of high-efficiency HFNC for oxygen supply, both deep sedation regimens in this randomized trial can be safely used for DFB procedure in elderly patients.However, the bolus administration of remimazolam combined with alfentanil proves to be superior to midazolam-alfentanil regimen in terms of higher success rate of sedation at a single induced dose and lower incidence of extra sleep within 6 hours postoperatively.Thus, the combination of remimazolam and alfentanil emerges as a more favorable clinical choice.

Figure 1 .
Figure 1.The flow diagram of the study.

Table 2
Clinical data of patients during DFB procedure.

Table 3
Postoperative follow-up and adverse events.